The World Trade Center health surveillance program: results of the first 10 years and implications for prevention.

BACKGROUND: The terrorist attacks on the World Trade Center (WTC) of September 11, 2001 resulted in the deaths of 2,823 persons. They also generated a long-lasting burden of multiple physical and mental health illnesses among the cohort of 50,000 rescue workers who responded to the attacks and in the 400,000 residents and workers in nearby areas of New York City. A comprehensive health surveillance program was developed from the first months after the accidents and was further developed in the subsequent ears. Individual exposure and health data were stored in ad hoc databases and produced epidemiological outcomes on the various exposure-related illnesses. METHODS: About 10 years of longitudinal assessment of this large cohort of WTC rescue and recovery workers, yielded data from participants in the WTC Screening, Monitoring, and Treatment Program. Police officers, firefighters, construction workers, and municipal workers were included in the cohort. Cumulative and annual incidence were estimated for various physical disorders including asthma, sinusitis, and gastroesophageal reflux disease, mental health disorders including depression, post-traumatic stress disorder [PTSD], and panic disorder. Respiratory functionality was also assessed. Exposure was characterized with qualitative parameter including working on the pile and being engulfed in the dust cloud, and quantitative parameters including the time of arrival on site and the exposure duration. RESULTS: Upper and lower respiratory conditions such as rhinosinusitis and asthma have been found in a significant number of people in WTC-exposed populations. A lack of appropriate respiratory protection may have contributed to these effects. Other commonly observed physical health conditions include gastro-esophageal reflux disease, obstructive sleep apnea and musculo-skeletal injuries. Many WTC-exposed individuals also suffer from mental health conditions, primarily post-traumatic stress disorder, depression, panic disorder, and substantial stress reaction. Recent studies suggest that WTC exposure may increase the risk of cancer and of mortality from cardiac disease. CONCLUSION: Ten years of systematic health surveillance after the 9/11 WTC attacks, show long lasting burden of physical and mental health problems. Continued monitoring and treatment of this population is needed for early diagnoses of initial clinical conditions that can be treated more effectively. The experience of September 11 offers also indications on how to approach the acute and delayed health effects of civilian catastrophes. Critical lessons are derived about the importance of having trained responders--medical and non-medical--in place in advance of disasters, and about the need to proceed with adequate exposure assessment in a timely manner.

The achievements of a multiservice project for older homeless people.

This report of the achievements of an experimental multiservice center in London for older street people begins with reviews of the types of long-term accommodation available for resettlement and the work of its outreach team, 24-hour open access rooms, and residential, assessment, and resettlement services. Two outcomes are examined: whether users returned to the streets and whether they were resettled in long-term housing. Those with alcohol dependency were most difficult to resettle. Logistic regression analyses of the factors influencing the two outcomes indicate that the duration of residence in the center was the the predominant influence.

Evidence for limited B-lymphopoiesis in adult rabbits.

Rabbits are born with a limited VDJ gene repertoire formed primarily by rearrangement of one VH gene, VH1. The VDJ genes are undiversified at birth but become diversified by approximately 2 mo of age. To investigate more closely the time during which this diversity occurs, we determined the nucleotide sequences of VDJ genes from peripheral blood leukocytes taken from young rabbits at various time points, and we examined the extent of the diversification of the VDJ genes. At 4 wk of age there were, on average, 3 nucleotide changes per VH region, with approximately 75% of the genes showing some diversification. The number of nucleotide changes per VH region increased to 12 by 6-8 wk of age, and all but 1 of the 35 sequences analyzed were diversified. Because only a limited number of genes can be examined by nucleotide sequence analysis, we used an RNase protection assay to examine a large number of genes and we determined the level of undiversified VH1 mRNA in lymphoid organs of both young and adult rabbits. In young rabbits, we found a high level of undiversified VDJ genes, but the level was greatly reduced by 2 mo of age. By adulthood, essentially all VDJ genes of cells from appendix, peripheral blood, and bone marrow were diversified. Because we had expected B lymphopoiesis to be ongoing in the bone marrow of adult rabbits, we were surprised not to find undiversified VDJ genes from the newly generated B cells. Therefore, we searched for evidence of ongoing B lymphopoiesis in bone marrow by isolating and examining circular DNA for the presence of VD and DJ recombination signal joints. We found highly reduced levels of recombination signal joints in bone marrow of adult rabbits relative to the levels found in bone marrow of newborn rabbits. These data indicate that limited VD and DJ gene rearrangements occur in bone marrow of adult rabbits, and we therefore suggest that B lymphopoiesis is limited in adults.

Cross-talk between ceramide and PKC activity in the control of apoptosis in WEHI-231.

WEHI-231, a murine B-cell lymphoma, readily undergoes programmed cell death following surface immunoglobulin (Ig) cross-linking [1]. Ceramide has been shown to induce apoptosis in WEHI-231 following its exposure to anti-lg antibodies, dexamethasone, and irradiation [2]. Recently, Haimovitz-Friedman et al. have demonstrated in endothelial cells that PMA not only prevented ceramide mediated apoptosis, but inhibited the generation of ceramide following irradiation [3]. In this paper we use highly specific PKC inhibitors to explore the connection between PKC activity, ceramide signaling and apoptosis. Both chelerythrine chloride and calphostin C triggered rapid apoptosis in WEHI-231 and acted in synergy with exogenous ceramide to induce apoptosis. Detailed studies of chelerythrine's mechanism of action revealed that 30 minutes following addition of 10 microM chelerythrine, sphingomyelin and phosphatidylcholine (PC) mass decreased confirming our previous findings of neutral, but not acidic, sphingomyelinase activation following treatment with PKC inhibitors [4]. The novel observation that inhibition of PKC isoforms present in WEHI-231 leads to a rapid rise in cellular ceramide as a results of sphingomyelin hydrolysis further suggests an antagonistic relationship between PKC activity and ceramide in the signaling events preceding apoptosis.

Transchromosomally derived Ig heavy chains.

During an immune response, activated B cells undergo isotype switching and begin to express isotypes other than IgM and IgD. Isotype switching occurs when downstream C gamma, C alpha, or C epsilon genes are rearranged into the S mu chromosomal region, resulting in the deletion of the region in between. These rearrangements usually occur in cis, i.e., intrachromosomally. In previous studies, we analyzed allotypic specificities of rabbit secretory IgA and identified a substantial number of IgA heavy chains with VH and C alpha allotypes that were encoded by VH and C alpha genes in trans. In those studies, however, we could not determine whether the trans association of VH and C alpha occurred during VDJ gene rearrangement or during isotype switching. Here, we cloned rabbit cDNA which encodes these trans IgA heavy chains and determined the chromosomal origin of the VH, JH, and C alpha regions. To determine whether the trans association occurred during VDJ gene rearrangement, we analyzed the nucleotide polymorphism of the JH region and the VH allotype encoded by the cDNA. We found that the VH and JH genes used in the VDJ gene rearrangements were from the same chromosome, indicating that the VH, D, and JH gene rearrangements occurred in cis. Furthermore, we analyzed the DNA polymorphisms of JH and C alpha and showed that the VDJ and C alpha genes encoding the trans IgA molecules were derived from different parental chromosomes. We suggest that the trans association occurred during isotype switching. This study shows that VH and CH can associate transchromosomally as part of a normal immune response.

Generating the antibody repertoire in rabbit.

We describe a model for B cell development and generation of the antibody repertoire in rabbits. In this model, B cells develop early in ontogeny, migrate to GALT, and undergo the first round of diversification by a somatic gene conversion-like process and by somatic mutation. We designate the repertoire developed by this mechanism as the primary antibody repertoire and it is this repertoire that makes the rabbit immunocompetent. We invoke GALT as the site for development of the primary repertoire because (1) surgical removal of GALT from neonatal rabbits results in highly immunocompromised animals, (2) in germfree rabbits essentially no lymphoid development occurs in GALT and the rabbits are immunoincompetent, and (3) the follicular development of rabbit GALT is highly similar to that of the chicken bursa, the site in which the primary antibody repertoire develops by somatic gene conversion in chicken. We suggest that once the primary antibody repertoire is formed, it is maintained by self-renewing CD5+ B cells and is expanded to a secondary antibody repertoire after the B cells encounter antigen.

Effect of immunization with Theiler's virus on the course of demyelinating disease.

Intracerebral (i.c.) inoculation of susceptible mice with Theiler's murine encephalomyelitis virus (TMEV) results in a demyelinating disease similar to human multiple sclerosis (MS). Mice develop a strong immune response to TMEV and the disease is believed to be immune-mediated. In order to investigate the effects of the immune response to TMEV on the course of demyelination, we immunized host mice with UV-inactivated TMEV at various time periods in relation to intracerebral inoculation with live TMEV. Here, we show that subcutaneous immunization of mice with TMEV prior to infection with virus is able to protect susceptible, SJL/J mice from demyelinating disease. This protective effect appears to be long-lasting; immunization greater than 90 days prior to i.c. inoculation of the virus protects mice from subsequent infection. However, immunization of mice after i.c. infection with TMEV does not confer protection, but rather exacerbates the disease symptoms. Thus, this system offers a model for studying viral capsid proteins and/or epitopes which are involved in either protection from disease or immune-mediated pathogenesis leading to myelin destruction in susceptible mice.

Identification and localization of a limited number of predominant conformation-independent antibody epitopes of Theiler's murine encephalomyelitus virus.

Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease in mice is a well established animal model for human multiple sclerosis (MS). Identification of pathogenic epitopes may be helpful in understanding the pathogenesis of this immune-mediated disease. In order to analyze the viral epitopes, we have generated approx. 150 recombinant lambda gt11 clones expressing various capsid areas of TMEV. Six predominant areas, ranging from 13-26 amino acid residues, (3 in VP1, 2 in VP2 and 1 in VP3) are readily recognized by conformation-independent antibodies from virus-infected mice. These areas have been designated as A-1A (VP1 13-27th residues), A-1B (VP1 145-167), A-1C (VP1 251-276), A-2A (VP2 2-14), A-2B (VP2 165-179), and A-3A (tentatively VP3 24-43). Antibodies from TMEV-infected susceptible SJL/J mice strongly react with A-1B, A-2A and A-2B, in contrast to antibodies from resistant BALB/c mice which mainly recognize A-1A and A-2A. Interestingly, the reactivity pattern of antibodies from TMEV-infected mice are somewhat different from that of antibodies from TMEV-immunized mice. Although the majority of antibodies in TMEV-infected mice recognizes conformation-dependent epitopes, the differential recognition of the conformation-independent antibody epitopes by susceptible mice may play a role in TMEV-induced demyelination.

Detection of restricted predominant epitopes of Theiler's murine encephalomyelitis virus capsid proteins expressed in the lambda gt11 system: differential patterns of antibody reactivity among different mouse strains.

Intracerebral injection of mice with Theiler's murine encephalomyelitis virus results in chronic demyelination in susceptible strains, and serves as a model system for the study of multiple sclerosis. The role of individual epitopes in the disease process remains to be elucidated. Random fragments of DNA from the viral capsid protein genome covering the coding regions from VP1, VP2, and VP3 have been expressed in the lambda gt11 vector system. Fusion proteins from the clones were expressed and probed with antibodies from both resistant and susceptible strains of mice. Each strain displays a distinctive pattern with certain fusion proteins recognized by all of the strains and others recognized uniquely by either the susceptible or the resistant strains.